Effects Of Single Nucleotide Polymorphisms Research Articles

Abstract 3132: Single nucleotide polymorphisms (SNPs) in PD-L1 as predictive biomarkers for checkpoint inhibitor based-immunotherapy in caucasian patients with advanced NSCLC

Abstract Effective predictive biomarkers are needed for checkpoint inhibitors (ICI) based-immunotherapy in non-small-cell lung cancer (NSCLC). This study aims to evaluate whether single nucleotide polymorphisms (SNPs) in programmed cell death-ligand 1 (PD-L1) might effectively predict tumor response to ICI in Caucasian patients with advanced NSCLC. Peripheral blood samples and clinico-pathological data were prospectively collected from advanced NSCLC patients treated with anti-Programmed cell death protein 1 (PD-1) inhibitor nivolumab. rs822336, rs2282055 and rs4143815 PD-L1 SNPs were analysed based on previous reports available in the literature. PD-L1 SNPs were analysed following DNA extraction from stored peripheral blood lymphocytes by Taqman Real-Time PCR assay. Presence of PD-L1 SNPs were correlated with clinico-pathological data. Mechanisms underlying the effect of PD-L1 SNPs on PD-L1 expression were analysed in vitro utilizing five NSCLC cell lines, RNA expression and flow cytometry analysis as well as PROMO bioinformatic tool. PD-L1 SNPs localization were analysed utilizing Ensembl genome browser. Differences were considered statistically significant with p value< 0.05. Twenty-eight patients were included in the study. rs2282055 was present as wild type (wt) TT (rs2282055>T), GT and GG genotype in 56.25%, 34.38% and 9.38%, respectively, of patients. On the other hand, rs822336 was present as wt GG (rs822336>G), GC and CC genotype in 28.13%, 37.50% and 34.38%, respectively, of patients. Progression free survival (PFS) was significantly correlated with presence of both PD-L1 SNPs rs2282055 and rs822336 but not with rs4143815. Patients carrying GG either for rs2282055 or rs822336 had a significantly (p=0.0434 and p=0.0131, respectively) shorter PFS as compared to those carrying other PD-L1 SNP genotypes. NSCLC cell lines carrying either GG for rs2282055 or rs822336 significantly (p<0.05) expressed a higher level of PD-L1 expression as compared to cells with other PD-L1 SNP genotypes. Interferon gamma treatment induced PD-L1 expression regardless of PD-L1 SNPs. rs822336 and rs2282055 mapped in enhancer-promoter and intronic regions of PD-L1 gene, respectively. rs822336 was further investigated because of its highest clinical significance and gene localization. Twelve transcription factors were identified to potentially bind rs822336. Two of them discriminated between alternative alleles at the SNP locus and are further under investigation. Previous studies have shown the role of SNPs in cancer patient outcome as well as in mRNA and protein expression changing. In the present study we demonstrated that some of PD-L1 SNPs can affect the basal expression of PD-L1. These results have clinical significance since PD-L1 SNPs predict tumor response to nivolumab-based immunotherapy in Caucasian patients with advanced NSCLC. Citation Format: Francesco Sabbatino, Giovanna Polcaro, Luigi Liguori, Valentina Manzo, Valeria Conti, Jessica Dal Col, Anita Vergatti, Cristiana Stellato, Vincenzo Casolaro, Amelia Filippelli, Soldano Ferrone, Stefano Pepe. Single nucleotide polymorphisms (SNPs) in PD-L1 as predictive biomarkers for checkpoint inhibitor based-immunotherapy in caucasian patients with advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3132.

A hypertension patient-derived iPSC model demonstrates a role for G protein-coupled estrogen receptor in hypertension risk and development.

Hypertension (HTN) is a polyfactorial disease that can manifest severe cardiovascular pathologies such as heart failure or stroke. Genome-wide association studies (GWAS) of HTN indicate that single-nucleotide polymorphisms (SNPs) contribute to increased risk for HTN and resistance to some HTN drug regimens (Hiltunen TP et al., J Am Heart Assoc 4: e001521, 2015; Le MT et al., PLoS One 8: e52062, 2013; McDonough CW et al., J Hypertens 31: 698-704, 2013; Vandell AG et al., Hypertension 60: 957-964, 2012). However, cellular mechanistic insights of such SNPs remain largely unknown. Using a bank of induced pluripotent stem cells (iPSCs) derived from patients with HTN and CRISPR/Cas9-mediated gene-editing approach, we investigated the effects of a female HTN risk-associated SNP (rs1154431) of the G protein-coupled estrogen receptor (GPER) (Bassuk SS, Manson JE., Clin Chem 60: 68-77, 2014) in vascular endothelial cells. Although GPER1 deletion reduced endothelial nitric oxide synthase (eNOS) activation in iPSC-derived endothelial cells (iECs), the polymorphism itself did not significantly affect eNOS and NO production in a comparison of isogenic hemizygous iECs expressing either normal (P16) or HTN-associated (L16) GPER. Interestingly, we demonstrate for the first time that GPER plays a role in regulation of adhesion molecule expression and monocyte adhesion to iECs. Moreover, the L16 iECs had higher expression of inflammation genes than P16 iECs, implying that the risk variant may affect carrier individuals through increased inflammatory activity. This study further indicates that iPSCs are a useful platform for exploring mechanistic insights underlying hypertension GWAS endeavors.

Effect of Expressions and SNPs of Candidate Genes on Intramuscular Fat Content in Qinchuan Cattle.

Simple SummaryIntramuscular fat (IMF), which characterizes the marbling, is a key meat quality trait in the beef industry. In this study, we validated the effect of the expression levels and single nucleotide polymorphisms (SNPs) of AKIRIN2, TTN, EDG1, and MYBPC1 genes on IMF content in Chinese Qinchuan cattle. The results showed that the expression levels of these genes could affect the IMF content, and the SNP in EGD1 could affect the IMF content in Qinchuan. The information of this study may be applied to effective marker-assisted selection, to increase the levels of marbling in Qinchuan beef production.Marbling is characterized by the amount and distribution of intramuscular fat (IMF). The AKIRIN2, TTN, EDG1, and MYBPC1 genes are well-known marbling-related genes, which were first identified in Japanese Black beef cattle. The objectives of this study were to analyze the correlation of the expression levels of these genes in the longissimus muscle (LM) with IMF content, and the associations between the single nucleotide polymorphisms (SNPs) in these genes and IMF content in Chinese Qinchuan cattle (n = 350). The association analyses showed that the g.42041062G>T SNP in the EDG1 gene was significantly associated with IMF content in Qinchuan (p < 0.05). Further, the expressions of the EDG1 and MYBPC1 were up-regulated (p < 0.05) in LM of Qinchuan cattle group with low IMF content. Down-regulations of the AKIRIN2 and TTN genes (p < 0.05 and p < 0.01, respectively) were observed in the Qinchuan cattle group with high IMF content. These results suggest possible effects of the expression levels of selected genes on IMF content in the LM, and the g.42041062G>T SNP in the EDG1 gene might be useful as a molecular marker for IMF content in Qinchuan.

Vitamin D Pathway Genetic Variation and Type 1 Diabetes: A Case-Control Association Study.

Vitamin D has immunomodulatory effects, and its deficiency has been implicated in the autoimmune process of type 1 diabetes. Serum vitamin D levels are influenced by variants in genes involved in the synthesis, transport, hydroxylation and degradation of vitamin D. The aim of this study was to assess if single nucleotide polymorphisms (SNPs) at the DHCR7 (rs12785878), GC (rs2282679), CYP2R1 (rs2060793) and CYP24A1 (rs6013897) loci are associated with type 1 diabetes in the Portuguese population. Genotype and allele frequencies were determined in 350 cases of type 1 diabetes and in 490 controls. The frequency of each SNP alone was not significantly different between patients and controls. However, the combined analysis of the four SNPs showed that minor alleles of these variants clustered more frequently in patients. The proportion of individuals with three or more minor alleles was significantly higher in patients than in controls (56.3% vs. 48.5; odds ratio (OR) 1.37; 95% confidence interval (CI) 1.04–1.81; p-value 0.027). These results suggest a cumulative effect of SNPs at the DHCR7, GC, CYP2R1 and CYP24A1 loci on the susceptibility to type 1 diabetes, due to the roles of these genes in the vitamin D metabolic pathway.

Identifying the Potential Mechanism of Action of SNPs Associated With Breast Cancer Susceptibility With GVITamIN.

In the last decade, a large number of genome-wide association studies have uncovered many single-nucleotide polymorphisms (SNPs) that are associated with complex traits and confer susceptibility to diseases, such as cancer. However, so far only a few heritable traits with medium-to-high penetrance have been identified. The vast majority of the discovered variants only leads to disease in combination with other still unknown factors. Furthermore, while many studies aimed to link the effect of SNPs to changes in molecular phenotypes, the analysis has been often focused on testing associations between a single SNP and a transcript, hence disregarding the dysregulation of gene regulatory networks that has been shown to play an essential role in disease onset, notably in cancer. Here we take a systems biology approach and develop GVITamIN (Genetic VarIaTIoN functional analysis tool), a new statistical and computational approach to characterize the effect of a SNP on both genes and transcriptional regulatory programs. GVITamIN exploits a novel statistical approach to combine the usually small effect of disease-susceptibility SNPs, and reveals important potential oncogenic mechanisms, hence taking one step further in the direction of understanding the SNP mechanism of action. We apply GVITamIN on a breast cancer cohort and identify well-known cancer-related transcription factors, such as CTCF, LEF1, and FOXA1, as TFs dysregulated by breast cancer-associated SNPs. Furthermore, our results reveal that SNPs located on the RAD51B gene are significantly associated with an abnormal regulatory activity, suggesting a pivotal role for homologous recombination repair mechanisms in breast cancer.

GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect β Cell Insulin Secretory Capacity and Apoptosis Through GLP-1.

The increased secretion of glucagon-like peptide-1 (GLP-1) after Roux-en-Y gastric bypass (RYGB) is regarded as the main reason for the improvement of blood glucose. However, the single-nucleotide polymorphisms (SNPs) of GLP-1 Receptor (GLP1R) impair receptor function, subsequently affecting β cell insulin secretion function, ultimately affecting the efficacy of RYGB. In this study, we revealed that two SNPs in GLP1R gene, rs3765467 and rs10305492, could significantly reduce the insulin secreted by β cells and the cyclic AMP concentration, whereas promote β cell apoptosis. Under high glucose exposure, rs3765467 and rs10305492 impaired β cell secretion of insulin and β cell viability in the same way; in other words, GLP1R rs3765467 and rs10305492 exert an effect on pancreatic β cell glucose-stimulated insulin secretion. Moreover, GLP-1 antagonist Exendin (9-39) further enhanced, whereas GLP-1 agonist Exendin-4 partially attenuated the effects of SNPs on the functions and apoptosis of β cells. In conclusion, the rs3765467 and rs10305492 SNPs in GLP1R show to exert a critical effect on regulating insulin secretory capacity of β cells and β cell mass. Through leading to the dysfunction and apoptosis of β cells, GLP1R rs3765467 and rs10305492 might also impair GLP-1 interaction with GLP1R, therefore attenuating the therapeutic effect of RYGB.

Association of the melanocortin 4 receptor (MC4R) gene polymorphism with growth traits of Hu sheep

Abstract In this study, Single Nucleotide Polymorphisms (SNPs) within the full length of the melanocortin 4 receptor (MC4R) gene in Hu sheep were detected and the functional SNPs associated with growth traits of Hu sheep were screened. Using a total of 202 female Hu sheep samples, this study investigated the genetic structure and genetic diversity of the Hu sheep population using PCR amplification, sequencing, and sequence analysis. We analyzed the association between SNPs and body weight and body size traits of Hu sheep and further studied the effect of MC4R gene SNPs on gene transcriptional activity. We found 19 SNPs in the MC4R gene of the Hu sheep population. Furthermore, we observed that the two SNPs (g.706 C→A, g.732 C→G) in the MC4R gene were significantly correlated with the adult height of female Hu sheep. The results of dual-luciferase reporter assay showed that the MC4R gene SNPs (g.706 C→A) had no significant effect on the activity of luciferase (P > 0.05), while the SNPs g.732 C→G showed significant effect (P

Association Study of Genetic Variants in Autophagy Pathway and Risk of Non-syndromic Cleft Lip With or Without Cleft Palate.

Although genetic variants in autophagy pathway genes were associated with the risk of oral cancers and early development in embryos, their associations with non-syndromic cleft lip with or without cleft palate (NSCL/P) risk remained unclear. A two-stage case-control study (2,027 NSCL/P cases and 1,843 controls) was performed to investigate the associations between single nucleotide polymorphisms (SNPs) in 23 autophagy pathway genes and NSCL/P susceptibility. The logistic regression model was used to calculate effects of SNPs on NSCL/P susceptibility. Gene-based analysis was performed via the sequence kernel association test (SKAT) and multi-marker analysis of genomic annotation (MAGMA) methods. Expression quantitative trait loci (eQTL) analysis was conducted using NSCL/P lip tissue samples. Gene expression during embryonic development was evaluated using RNA-Seq. Functional roles were explored by luciferase activity assay, cell apoptosis, proliferation, and cycle in vitro. Rs2301104 in HIF1A was significantly associated with NSCL/P susceptibility in the combined analysis (OR: 1.29, 95% CI: 1.09–1.29, P = 3.39 × 10–03), and showed strong evidence of association heterogeneity (P = 9.06 × 10–03) with obvious association in the female (OR: 1.80; 95% CI: 1.32–2.45; P = 1.79 × 10–04). The G allele of rs2301104 was associated with enhanced transcription activity and high expression of HIF1A compared with that of C allele. Moreover, rs2301104 exhibited an eQTL effect for HIF1A with its GC/CC genotypes associated with decreased HIF1A expression compared with those with GG genotypes (P = 3.1 × 10–2). Knockdown of HIF1A induced cell apoptosis and inhibited cell proliferation in human embryonic palate mesenchyme (HEPM) and human oral epithelium cells (HOEC). This study demonstrated that rs2301104 in autophagy pathway gene HIF1A was associated with susceptibility of NSCL/P.

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Effects of polymorphisms in the endothelin receptor B &lt;i&gt;subtype 2&lt;/i&gt; gene on plumage colour in mule ducks

The aim of the present study was to investigate the effect of a single nucleotide polymorphism (SNP) of the endothelin receptor B subtype 2 (EDNRB2) gene on plumage coloration in mule ducks. Test mating (white Tsaiya × white Muscovy ducks) in combination with polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) was performed to investigate the effect of non synonymous SNPs in two maternal lines (a conservation and a selection population) on plumage coloration in mule ducks. One non synonymous SNP (c.995G&gt;A) was identified in white Muscovy ducks and white Tsaiya ducks by PCR high resolution melting (PCR HRM) and DNA sequencing. Genotyping results showed that the c.995G&gt;A locus is associated with plumage colour in two maternal populations of white Tsaiya ducks. Further, the maternal genotype of c.995G&gt;A SNP affects the plumage colour of mule ducks. Therefore, the polymorphisms within the EDNRB2 gene at c.995G&gt;A in white Tsaiya ducks may be used in marker assisted selection to improve the plumage colour of mule ducks.&#x0D; Keywords: Muscovy drakes, polymerase chain reaction restriction fragment length, single nucleotide polymorphism, Tsaiya ducks

Association of Polymorphisms in Cytokine genes with susceptibility to Precancerous Lesions and Cervical Cancer: A systematic review with meta-analysis

ABSTRACT Objectives: This study investigated the relationship between single-nucleotide polymorphisms (SNPs) in cytokine genes and the susceptibility to Squamous Intraepithelial Lesions (SIL), cervical cancer and HPV infection through a systematic review with meta-analysis. To verify the effect of SNPs, we also analyzed the transcription factor binding affinity using bioinformatics tools. Methods: Seven electronic databases (MEDLINE, Scielo, BIREME, PubMed, Scopus, Web of Science and Science Direct) were searched for case–control studies. Results: A total of 35 relevant case–control studies were meta-analyzed, including 7 cytokine genes and 15 SNPs. SNPs in IL-17A (rs2275913, rs3748067); IL-17 F (rs763780); IL-12A (rs568408); IL-12B (rs3212227); TNFA (rs1800629, rs361525); IL-1B (rs16944); IL-6 (rs1800795); IL-10 (rs1800896) genes were associated with increased risk for cervical cancer. No association was observed between meta-analyzed polymorphisms and SIL. Additional bioinformatics analysis suggested a possible transcriptional regulation pathway of the TNFA and IL-10 genes through the MZF1 (TNFA −308 G > A and IL-10 − 1082A>G) and ZNF263 (TNFA −238 G > A) transcription factors binding. Conclusion: Overall, 10 SNPs in cytokine genes were associated with increased risk for cervical cancer. Therefore, in our meta-analysis, these SNPs demonstrated to be potential biomarkers for predicting or identifying cases of high risk for SIL and cervical cancer.

A comprehensive evaluation of association between homocysteine levels and single nucleotide polymorphisms with hypertension risk: A protocol of systematic review and network meta-analysis.

According to the relevant reports that single nucleotide polymorphisms (SNPs) may contribute to change of homocysteine (HCY) levels and increase the risk of hypertension (HTN). During the inconsistent results, this meta-analysis purpose is systematically review and synthesized relevant data on HCY levels and SNPs in HTN. The systematic search database, from the following database to find out the association studies of SNPs and HTN publications up until March 2020 from the databases of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), the Chinese Science and Technology Periodical Database (VIP) and Wan fang databases, and Chinese Biomedical Literature Database (CBM). Network meta-analysis and Thakkinstian's algorithm were used to select the most appropriate genetic model, along with false positive report probability (FPRP) for noteworthy associations. All statistical analyses were calculated with STATA software (version 14.0; StataCorp, College Station, TX). This meta-analysis will provide high-quality evidence to the effects of SNP on HTN and levels of HCY, and find between SNPs and HTN susceptibility on in all the genetic models, and choose the best one. This meta-analysis will research which SNP is the most correlated with HTN risk. INPLASY202050002.

Association of genetic variants in lncRNA GAS5/miR-21/mTOR axis with risk and prognosis of coronary artery disease among a Chinese population.

BackgroundAllowing for the significance of single nucleotide polymorphisms (SNPs) in reflecting disease risk, this investigation attempted to uncover whether SNPs situated in lncRNA GAS5/miR‐21/mTOR axis were associated with risk and prognosis of coronary heart disease (CHD) among a Chinese Han population.MethodsAltogether 436 patients with CHD were recruited as cases, and meanwhile, 471 healthy volunteers were included into the control group. Besides, SNPs of GAS5/MIR‐21/mTOR axis were genotyped utilizing mass spectrometry. Chi‐square test was applied to figure out SNPs that were strongly associated with CHD risk and prognosis, and combined effects of SNPs and environmental parameters on CHD risk were evaluated through multifactor dimensionality reduction (MDR) model.ResultsSingle nucleotide polymorphisms of GAS5 (ie, rs2067079 and rs6790), MIR‐21 (ie, rs1292037), and mTOR (rs2295080, rs2536, and rs1034528) were associated with susceptibility to CHD, and also Gensini score change of patients with CHD (P < .05). MDR results further demonstrated that rs2067079 and rs2536 were strongly interactive in elevating CHD risk (P < .05), while smoking, rs6790 and rs2295080 showed powerful reciprocity in predicting Gensini score change of patients with CHD (P < .05).ConclusionSingle nucleotide polymorphisms of lncRNA GAS5/miR‐21/mTOR axis might interact with smoking to regulate CHD risk, which was conducive to diagnosis and prognostic anticipation of CHD.

Polymorphisms in Neuronal Growth Regulator 1 and Otoancorin Alternate the Susceptibility to Lung Cancer in Chinese Nonsmoking Females.

Cell adhesion molecules (CAMs) play crucial roles in the genesis and progress of tumor. We investigated the effects of single nucleotide polymorphisms (SNPs) of CAMs, neuronal growth regulator 1 (NEGR1), and Otoancorin (OTOA) on lung cancer susceptibility in Chinese nonsmoking females. Logistic regression and Cox regression analyses were conducted to investigate the effects of SNPs and environmental factors. For rs3102911, genotype TT carriers decreased the risk of lung cancer with an odds ratio (OR) of 0.635. AA genotypes of rs741718 increased the risk of lung cancer with an OR of 3.527. In stratified analysis, genotype AA carriers of rs741718 had a high susceptibility to lung adenocarcinoma compared with GG and AG genotypes. Analyses of association between SNPs and clinical characteristics revealed that rs3102911 as a protective factor and rs741718 as a risk factor influenced the lung cancer occurrence and progression in nonsmoking females.

Genetic variants in Ras/Raf/MEK/ERK pathway are associated with gastric cancer risk in Chinese Han population.

The dysregulation of Ras/Raf/MEK/ERK pathway governs occurrence and progression of cancers. In previous studies, genome-wide association studies (GWAS) have identified multiple gene loci related to gastric cancer. However, a great many genetic loci have been missed due to multiple statistical comparisons of GWAS. In this study, Multi-marker Analysis of GenoMic Annotation (MAGMA) was applied to analyze genes in Ras/Raf/MEK/ERK pathway and their single nucleotide polymorphisms (SNPs) based on Chinese GWAS including 1625 gastric cancer cases and 2100 controls. The SNP effects on gastric cancer susceptibility were calculated on the basis of a logistic regression model. Expression quantitative trait loci (eQTL) analysis was performed based on the genotype-tissue expression (GTEx) project. We identified that three SNPs in MAP2K1, rs4287513, rs76906202 and rs11631448 were markedly associated with gastric cancer risk (rs4287513: OR = 1.30, 95% CI = 1.10-1.54, P = 1.92 × 10-3; rs76906202: OR = 0.87, 95% CI = 0.79-0.96, P = 3.72 × 10-3; rs11631448: OR = 1.21, 95% CI = 1.05-1.39, P = 6.74 × 10-3). All the loci were eQTLs for MAP2K1 in normal gastric samples. Moreover, the low expression of MAP2K1 was significantly associated with poor survival in gastric cancer patients. Thus, MAP2K1 might represent a key gene related to gastric cancer in Ras/Raf/MEK/ERK pathway, whereas SNPs in MAP2K1 confer gastric cancer susceptibility by having biological effects on the MAP2K1 expression.

Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy.

Angiogenesis is essential for growth, progression, and metastasis of solid tumors. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) and angiopoietin (ANGPT)/ tyrosine kinase endothelial (TEK) signaling plays an important role in regulating angiogenesis. Very little is known about the effects of single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes on treatment outcome in head and neck squamous cell carcinoma (HNSCC). Therefore, we evaluated the association between SNPs in ANGPT1, ANGPT2, TEK, VEGF, VEGFR1, and VEGFR2 genes and five clinical endpoints in 422 HNSCC patients receiving radiotherapy alone or combined with chemotherapy. Multivariate analysis showed an association of ANGPT2 rs3739391, rs3020221 and TEK rs639225 with overall survival, and VEGF rs2010963 with overall and metastasis-free survival. VEGFR2 rs1870377 and VEGF rs699947 affected local recurrence-free survival in all patients. In the combination treatment subgroup, rs699947 predicted local, nodal, and loco-regional recurrence-free survival, whereas VEGFR2 rs2071559 showed an association with nodal recurrence-free survival. However, these associations were not statistically significant after multiple testing correction. Moreover, a strong cumulative effect of SNPs was observed that survived this adjustment. These SNPs and their combinations were independent risk factors for specific endpoints. Our data suggest that certain germline variants in ANGPT2/TEK and VEGF/VEGFR2 axes may have predictive and prognostic potential in HNSCC treated with radiation or chemoradiation.

The contribution of WTAP gene variants to Wilms tumor susceptibility.

Wilms tumor is the most frequently occurring pediatric renal malignancy. Wilms tumor suppressor-1-associated protein (WTAP) is a vital component of N6-methyltransferase complex involved in tumorigenesis. However, the roles of WTAP gene single nucleotide polymorphisms (SNPs) in Wilms tumor risk have not been clarified to date. We successfully genotyped three WTAP gene SNPs using TaqMan assay in 405 Wilms tumor patients and 1197 cancer-free controls of Chinese children. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to determine the effects of WTAP gene SNPs on Wilms tumor risk. Carriers of the rs1853259 G variant are less susceptible to developing Wilms tumor, with an adjusted OR of 0.78 (AG vs. AA: 95% CI=0.61-0.995, P=0.046). Single locus analysis of rs9457712 G>A and rs7766006 G>T, as well as the combined analysis of risk genotypes, failed to unveil an association with Wilms tumor risk, respectively. Stratified analysis of the three SNPs and their combined risk effects showed more significant relationships with Wilms tumor risk under certain subgroups. In all, we found weak evidence of the association between WTAP gene SNPs and the risk of Wilms tumor. Further replication studies with greater sample size and different ethnicities are necessary to verify our findings.

Nonreceptor protein tyrosine phosphatases (NRPTPs) gene family associates with the risk of hepatocellular carcinoma in a Chinese hepatitis B virus-related subjects.

Nonreceptor protein tyrosine phosphatases (NRPTPs) are reported to be associated with several human cancers, but their roles in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. Here, we integrated bioinformatics tools, population association analyses, and biological assays to systematically screen for potentially functional single nucleotide polymorphisms (SNPs) within the 17 NRPTPs genes and evaluate the effects of candidate SNPs on the risk of HCC or persistent HBV infection. A total of 790 HBV-related HCC cases and 1454 cancer-free controls were enrolled. Controls included 711 HBV persistent carriers and 743 spontaneously recovered subjects. Results demonstrated that PTPN4 rs9308777 (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06-1.49, P = .009) and PTPN12 rs350050 (OR = 1.26, 95% CI = 1.10-1.45, P = .001), were significantly associated with HCC risk, but not with persistent HBV infection risk. The cumulative risk effect of these two SNPs was more significantly increased the susceptibility to HCC (OR = 1.27, 95% CI = 1.14-1.41, P = 2.40 × 10-5 ). Subsequent biological assays further revealed the potential pathogenesis that PTPN4 rs9308777 might decrease the gene expression, and PTPN12 rs3750050 might promote cell proliferation by attenuating PTPN12's inhibitory activity on EGFR/ERK pathway. In summary, our integrative study highlights that PTPN4 and PTPN12 are significantly associated with HBV-related HCC risk, but do not influence persistent HBV infection. These findings shed light on the importance of the synergistic effects of regulatory and missense variants on the risk for HCC, and provide data to support personalized cancer medicine in the future.

Single Nucleotide Polymorphisms Related toLipoprotein Metabolism Are Associated withBlood Lipid Changes following RegularAvocado Intake in a Randomized Control Trialamong Adults with Overweight and Obesity

Avocados are rich in unsaturated fat and fiber; clinical trials have investigated their effects on metabolic disease. There is high variability in individual changes following avocado consumption, which may be in part due to individual genetic differences. Secondary analyses of the Persea americana for Total Health (PATH) Study were used to examine how single nucleotide polymorphisms (SNPs) impact blood lipid changes following a daily meal containing avocado compared with control. Adults (n=115, 37% male) aged 25-45 y with overweight and obesity were randomly assigned to receive a daily isocaloric meal with (intervention) or without (control) a standardized amount (males: 175g; females: 140g) of avocado for 12 wk. Control meals were higher in saturated fat (17% of energy compared with 7%) and lower in fiber (4g compared with 16g) than intervention meals. Whole venous blood was taken at baseline and 12 wk to determine total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) concentrations. Seventeen SNPs in 10 genes related to lipoprotein metabolism were genotyped. Effects of SNP, diet, and SNP-diet interactions were determined using general linear models. No group-by-time effects were detected for changes in TC (P=0.96), HDL cholesterol (P=0.28), or TG (P=0.06) over 12 wk. Three SNP-diet interactions were associated with final TC concentrations: ANGPTL3-rs10889337 (P=0.01), ANGPTL4-rs2278236 (P=0.02), and CD36-rs10499859 (P=0.01). SNPs in GCKR and LPL were associated with TC changes (P=0.01). The interaction between GCKR-rs1260326 and diet was such that C-homozygotes receiving avocado (n=23) had final TC concentrations that were significantly lower than the C-homozygotes in the control group (n=20) (P=0.02). Results from these exploratory analyses indicate that avocado consumption may help manage dyslipidemia in adults with overweight and obesity; however, effectiveness may differ by genetic profile. Understanding the role of genetic variation in variability following dietary intervention can potentially inform personalized nutrition recommendations.

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize TMPRSS2 and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs. Communicated by Ramaswamy H. Sarma